Nanocomposite drug eluting stents for inhibition of restenosis and thrombosis

 描述(由申请人提供)：目前的药物洗脱支架非常容易形成血栓(晚期支架血栓形成)，导致心脏病发作和死亡的风险显著增加。晚期支架血栓形成的风险增加是由于使用了抗增殖药物，这些药物损害了血管内皮化，使血液暴露在血栓形成的支架支架上。此外，用于促进药物释放的聚合物还会导致延迟愈合、支架支架内皮化受损以及最终导致支架血栓形成的超敏反应。使用不可降解的支架材料也会增加血栓形成，导致慢性炎症局部反应和长期的内皮功能障碍。尽管存在这些问题，研究人员仍在继续研究从可降解和不可降解支架中输送抗增殖药物。鉴于目前药物洗脱支架死亡风险的增加，迫切需要开发一种新型的可生物降解的支架，以抑制 再狭窄和目前的药物洗脱支架一样，还可以抑制血栓形成，加速再内皮化，并完全生物降解，从而持久防止血栓。这项建议的目的是制造和表征一种可生物降解的纳米复合材料药物洗脱支架，使用的聚合物是血液相容的，可以抑制血栓形成，并且可以传递一种自然产生的分子，已被证明在促进内皮化的同时抑制再狭窄。本项目的第一部分是制备和表征纳米复合药物洗脱支架。支架将通过将弹性聚合物与刚性纳米纤维聚合物相结合来制造，以制造具有类似于现有聚合物支架的机械性能的纳米复合支架。药物释放动力学将通过高效液相色谱来测量。力学性能将通过压缩测试和折叠支架压力来表征。降解性能将通过测量在磷酸盐缓冲盐水中浸泡后质量的变化来评估。我们还将通过检测血小板粘附性、全血凝结时间和流动状态下的血栓形成来评估这些支架的血液相容性。释放的药物对血管细胞增殖、迁移、蛋白表达和 流动状态下的保留率将被描述。在AIMS 2和3中，支架将在猪动物模型中进行测试。该项目的成功完成将证明我们的理念的可行性。新型支架的开发将具有重要意义，因为它将是第一个可生物降解的药物洗脱支架，它可以在不抑制再内皮化的情况下特异性地抑制由于新生内膜增生而导致的再狭窄，从而显著降低或消除支架血栓形成、心脏病发作和死亡的风险。这种支架的开发有可能减少重复血管干预的次数，降低死亡率，并显著降低医疗成本。此外，从这项建议中获得的信息也可以用于开发也容易堵塞和凝块形成的改进的血管装置。

 DESCRIPTION (provided by applicant): Current drug eluting stents are highly susceptible to blood clots forming (late stent thrombosis) leading to significantly increased risk of heart attack and death. The increased risk of late stent thrombosis is caused by the use of anti-proliferative drugs that impair endothelialization so that blood is exposed to thrombogenic stent struts. Furthermore, the polymers used to facilitate drug release can also cause delayed healing, impaired stent strut endothelialization, and hypersensitivity reaction that can culminate in stent thrombosis. Thrombosis is also increased by the use of non-degradable stent materials that results in chronic inflammatory local reactions and long-term endothelial dysfunction. Despite these problems, researchers continue to study the delivery of antiproliferative drugs from both degradable and non-degradable stents. Given the increased risk of death with current drug eluting stents, there is a critical need to develop a new type of biodegradable stent that inhibits restenosis as well as current drug eluting stents, but also inhibits thrombosis, accelerates re- endothelialization, and biodegrades completely for lasting clot prevention. The objective of this proposal is to fabricate and characterize a biodegradable nanocomposite drug eluting stent using a polymer that is hemocompatible, can inhibit thrombosis, and can deliver a naturally occurring molecule that has been shown to inhibit restenosis while promoting endothelialization. The first part of this project is to fabricate and characterize nanocomposite drug eluting stents. Stents will be made by combining an elastomeric polymer with a rigid nanofibrous polymer in order to fabricate nanocomposite stents with mechanical properties similar to existing polymeric stents. Drug release kinetics will be measured via high performance liquid chromatography. Mechanical properties will be characterized via compression testing and collapsed stent pressure. Degradation properties will be assessed by measuring the change in mass after soaking in phosphate buffered saline. We will also assess the hemocompatibility of these stents by examining platelet adhesion, whole blood clotting times, and thrombus formation under flow. The effect of the released drugs on vascular cell proliferation, migration, protein expression, and retention under flow will be characterized. In aims 2 and 3, stents will be tested in a porcine animal model. Successful completion of this project will demonstrate feasibility of our concept. Development of a new type of stent would be significant because it would be the first biodegradable drug eluting stent that can specifically inhibit restenosis due to neointimal hyperplasia without inhibiting re-endothelialization and therefore significantly reducing or eliminating the risk of stent thrombosis, heart attack, and death. Development of such a stent has the potential to reduce the number of repeat vascular interventions, decrease mortality rates, and significantly reduce healthcare costs. Furthermore, the information gained in this proposal could also be used to develop improved vascular devices that also are susceptible to occlusion and clot formation.